Selective MT sub(2) melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms

• Published in: The FASEB journal 1998-09, Vol.12 (12), p.1211-1220
• Main Authors: Dubocovich, M L, Yun, K, Al-Ghoul, WM, Benloucif, S, Masana, MI
• Format: Article
• Language: English
• ISSN: 0892-6638

This study demonstrates the involvement of the MT sub(2) (Mel sub(1b)) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt sub(1) and MT sub(2) melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 mu g/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC sub(50)=0.72 mu g/mouse; 0.98 plus or minus 0.08 h (n=15) maximal advance at 9 mu g/mouse]. Neither the selective MT sub(2) melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 mu /mouse, s.c.) nor luzindole (300 mu g/mouse, s.c.), which shows 25-fold higher affinity for the MT sub(2) than the mt sub(1) subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 mu g melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT sub(2) melatonin receptor subtype within the circadian timing system. We conclude that the MT sub(2) melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders. - Dubocovich, M. L., Yun, K., Al-Ghoul, W. M., Benloucif, S., Masana, M.I. Selective MT sub(2) melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms.